Submissions for variant NM_000038.6(APC):c.4591A>C (p.Asn1531His)

gnomAD frequency: 0.00001  dbSNP: rs771096141

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000574767	SCV000667527	uncertain significance	Hereditary cancer-predisposing syndrome	2016-03-25	criteria provided, single submitter	clinical testing	The p.N1531H variant (also known as c.4591A>C), located in coding exon 15 of the APC gene, results from an A to C substitution at nucleotide position 4591. The asparagine at codon 1531 is replaced by histidine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 70000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000574767	SCV000913135	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-03	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 1531 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV004561670	SCV001391652	uncertain significance	Familial adenomatous polyposis 1	2023-06-02	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with APC-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function. ClinVar contains an entry for this variant (Variation ID: 482326). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 1531 of the APC protein (p.Asn1531His).
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153739	SCV003843685	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
3DMed Clinical Laboratory Inc	RCV000677757	SCV000803913	uncertain significance	Gastrointestinal stromal tumor of small intestine	2017-07-31	no assertion criteria provided	clinical testing